Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System
Authors: Chigusa Morizane, Nozomu Machida, Yoshitaka Honma, Takuji Okusaka, Narikazu Boku, Ken Kato, Shogo Nomura, Nobuyoshi Hiraoka, Shigeki Sekine, Hirokazu Taniguchi, Naohiro Okano, Kensei Yamaguchi, Takuji Sato, Masafumi Ikeda, Nobumasa Mizuno, Masato Ozaka, Tomoko Kataoka, Makoto Ueno, Yuko Kitagawa, Masanori Terashima, Junji Furuse, Yusuke Sano, Kyoko Hasegawa, Ryo Sadachi, Kenichi Nakamura, Haruhiko Fukuda, Mitsuya Iwafuchi, Ryoji Kushima, Tetsuo Ushiku, Noriyoshi Fukushima, Nobuyuki Ohike, Yuki Katsuta, Keiya Okamura, Yasyuki Kawamoto, Hirofumi Shirakawa, Hironori Yamaguchi, Satoshi Shimizu, Hisahiro Matsubara, Yasushi Kojima, Keiji Sano, Kumiko Umemoto, Rika Sakai, Haruo Miwa, Kazuhiko Shioji, Shinya Kajiura, Takeshi Terashima, Kazuyoshi Ohkawa, Masahiro Tsuda, Akinori Asagi, Toshiyuki Suzuki, Nao Fujimori, Kentaro Kawakami, Yuji Akiyama, Yasuko Murakawa, Akihito Kawazoe, Chihiro Kondoh, Hiroshi Yabusaki, Kunihiro Tsuji, Atsuyuki Maeda, Takushi Yasuda, Takuya Hamakawa, Kazumasa Fujitani, Masahiro Goto, Ryouhei Kawabata, Yoshihiro Kakeji, Takashi Ohta, Hisashi Shinohara, Hiroki Fukunaga, Noriyuki Hirahara, Kazuaki Tanabe, Satoshi Oono, Yasuhiro Yuasa, Tsuyoshi Etoh, Masanobu Takahashi, Yusuke Amanuma, Motoo Nomura, Yuichiro Doki, Yoshiaki Nagatani, Hiroshi Ariyama
Journal: JAMA Oncology (2022)

Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC).To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system.This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020.In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks.The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation.Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN.Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm.Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.